Hindawi Publishing Corporation

Case Reports in Immunology

Volume 2014, Article ID 394754, 9 pages
http://dx.doi.org/10.1155/2014/394754

Case Report
Successful Management of Insulin Allergy and Autoimmune
Polyendocrine Syndrome Type 4 with Desensitization
Therapy and Glucocorticoid Treatment: A Case Report and
Review of the Literature

Joselyn Rojas,1,2 Marjorie Villalobos,1,2 María Sofía Martínez,1 Mervin Chávez-Castillo,1

Wheeler Torres,1 José Carlos Mejías,1 Edgar Miquilena,1 and Valmore Bermúdez1
1
Endocrine and Metabolic Diseases Research Center, School of Medicine The University of Zulia, Maracaibo 4004, Venezuela
2
Endocrinology Department, Maracaibo University Hospital (SAHUM), Maracaibo 4004, Venezuela

Correspondence should be addressed to Joselyn Rojas; rojas.joselyn@gmail.com

Received 26 August 2014; Accepted 30 October 2014; Published 19 November 2014

Academic Editor: Rajni Rani

Copyright © 2014 Joselyn Rojas et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction. Insulin allergy is a rare complication of insulin therapy, especially in type 1 diabetes mellitus (T1DM). Key
manifestations are hypersensitivity-related symptoms and poor metabolic control. T1DM, as well as insulin allergy, may develop
in the context of autoimmune polyendocrine syndrome (APS), further complicating management. Case Report. A 17-year-old
male patient, diagnosed with T1DM, was treated with various insulin therapy schemes over several months, which resulted in
recurrent anaphylactoid reactions and poor glycemic control, after which he was referred to our Endocrinology and Immunology
Department. A prick test was carried out for all commercially available insulin presentations and another insulin scheme was
designed but proved unsuccessful. A desensitization protocol was started with Glargine alongside administration of Prednisone,
which successfully induced tolerance. Observation of skin lesions typical of vitiligo prompted laboratory workup for other
autoimmune disorders, which returned positive for autoimmune gastritis/pernicious anemia. These findings are compatible with
APS type 4. Discussion. To our knowledge, this is the first documented case of insulin allergy in type 4 APS, as well as this particular
combination in APS. Etiopathogenic components shared by insulin allergy and APS beg for further research in immunogenetics
to further comprehend pathophysiologic aspects of these diseases.

1. Introduction a rare condition, yet it represents a substantial challenge for

Type 1 diabetes mellitus (T1DM) is an autoimmune disease
where adaptive immunity-mediated destruction of pancre-
atic 𝛽 cells leads to an absolute absence of insulin [1].
Infiltration of Langerhans islets by mononuclear cells, as
well as antipancreatic islet antibodies and circulating islet-
reactive T cells, is prominent features of this pathology [2].
Notwithstanding the key role played by genetic susceptibility
for the development of T1DM, environmental and nongenetic
factors are an equally relevant component in the pathophys-
iology of this disease [3]. Due to the irreversibility of the
damage to pancreatic 𝛽 cells, patients with T1DM require
lifetime insulin therapy to preserve adequate metabolic
control [4]. In these subjects, hypersensitivity to insulin is
attending physicians, since in these cases, the predominant
immune component attacks not only the pancreatic islet,
but also insulin itself, the main therapeutic measure for the
disease.
In early documented cases of insulin allergy, hypersensi-
tivity was developed in response to administration of animal-
origin insulins, which possess a great antigenic potential due
to alterations in their structure, presence of contaminants,
and highly immunogenic components such as C-peptide
and proinsulin [5–7]. Moreover, IgG anti-insulin antibodies
can induce a primary form of insulin resistance, progressive
dysglycemia, and lipoatrophy [5]. However, the introduction
of human recombinant insulins in the early 1980s has led
to a drastic decrease in incidence of these cases, currently
2 Case Reports in Immunology

Type I Type III Type IV

Wheals, flares, edema, and prutitus Arthus reaction, subcutaneous nodules Cell-mediated response
on site of injection after 4–12 h
Insulin

IgG

Inflammation mediators

I C1q
Mast
TH2 CD8
-6 5 ,
IL , IL-
-4

IL-
IL

4, TH1
IL-
13
B

Inflammation mediators
IgE-insulin specific

Figure 1: Types of hypersensitivity associated with insulin-related allergy reactions. Type I hypersensitivity reaction is characterized to be
a TH2-controlled IgE-insulin specific mediated process, with local edema, itching, wheals, and flares, which could also be associated with
angioedema. Type III hypersensitivity is mediated by antigen-antibody complex and recruitment of complement C1q, with subsequent edema,
necrosis, and nodule formation. Finally, Type IV reactions are CD8-cytotoxic specific with subcutaneous edema, itching, and hyperkeratosis.

estimated at <1% to 2.4% [8]. Clinically, manifestations range
from local reactions at the site of injection to severe cases
of potentially life-threatening generalized anaphylaxis, and
the disease has been described as type I hypersensitivity
(IgE-mediated) [9], type III (immune complex-mediated)
[10], and type IV delayed hypersensitivity to components
added to insulin preparations such as cresol, protamine, and
epoxy resin [7, 8, 10–25]; see Figure 1. Tendency to develop-
ing hypersensitivity towards insulin relies on its structural
modifications in comparison to endogenous insulin, which
would modify central tolerance for T lymphocytes [10–25]
(Table 1). Management of such cases involves a change of
insulin presentation, but, ultimately, most individuals are set
through a desensitization protocol [7, 26].
It has been observed that T1DM can coexist with other
autoimmune diseases, including vitiligo. The latter is an
autoimmune skin disorder characterized by loss of pigmen-
tation due to melanocyte destruction [27]. Several genetic
factors have been involved in its pathogenesis, including
polymorphisms in HLA-DRB1∗07:01, HLA-B∗44:03, HLA-
A∗02:01 y HLA-A∗33:01 [27], and other intrinsic defects in
melanocytes, which affect its ability to sustain UV stress [28].
Cellular immunity has been proved to participate in this
scenario, along with autoreactive CD8+ T cells which are
the effector cells in this disease [29]. The combination of
T1DM and vitiligo can be seen as part of the autoimmune
polyendocrine syndromes (APS), alongside various other
glandular autoimmune dysfunctions [30], with a prevalence
of 2–10% [16]. Classification of entities in the APS spectrum
is complex and is based on the distinct combinations of
autoimmunity-targeted organs [31]; see Table 2. In this broad
spectrum of autoimmune diseases, T1DM patients can also be
diagnosed with autoimmune thyroid disease (∼30%), celiac
disease (4–9%), autoimmune gastritis/pernicious anemia (5–
10%), and Addison’s disease (∼0.5%) [30, 31].
The following case concerns a teenage boy with T1DM,
vitiligo, and autoimmune gastritis, presenting with a severe
case of allergy to multiple insulins, managed with a desensi-
tization protocol.
2. Case Presentation
A 17-year-old teenager patient, from Los Puertos de Altagra-
cia community (Miranda municipality, Zulia state), who was
Case Reports in Immunology 3

Table 1: Insulin analogues and recombinant variations, structure, Table 1: Continued.

and related immunogenic reactions.
Immunogenic molecules Reaction type References
Immunogenic molecules Reaction type References Glargine insulin (Lantus)
s s
Regular human insulin
G I V E Q C C T S I C S L Y Q L E N Y C R
s s
s s
G I V E Q C C T S I C S L Y Q L E N Y C N
s s
s s
F V N Q H L C G S H L V E A L Y L V C G E R G F F Y T P K R
T R
s s
F V NQ H L C G S H L V E A L Y L V C G E R G F F Y T P K T I [11, 12, 21]
Insulin
Insulin I [8, 10–15] III [14]

III [15] Detemir insulin (Levemir)

s s
Crystalline insulin G I V E Q C C T S I C S L Y Q L E N Y C N
s s s s
G I V E Q C C T S I C S L Y Q L E N Y C N s s
s s F V N Q H L C G S H L V E A L Y L V C G E R G F F Y T P
s s
F V N Q H L C G S H L V E A L Y L V C G E R G F F Y T P K T C14 H28 O2

Insulin I [8, 16, 17] I [12, 22]

Porcine insulin Insulin III [14, 23]
s s
IV [22]
G I V E Q C C T S I C S L Y Q L E N Y C N
s s Metacresol I [24]
s s
F V N Q H L C G S H L V E A L Y L V C G E R G F F Y T P K A

Insulin I [8, 16] diagnosed with T1DM on October 2012 after a hyperglycemic
Bovine insulin crisis complicated with diabetic ketoacidosis, treated only
s s with fast-acting insulin (Crystalline) due to type I hyper-
G I V E Q C C A S V C S L Y Q L E N Y C N sensitivity to intermediate-lasting insulin NPH (Neutral Pro-
s s
tamine Hagedorn), and long-lasting insulin Glargine (Lan-
s s
tus). He was referred to the Endocrinology and Immunology
F V N Q H L C G S H L V E A L Y L V C G E R G F F Y T P K A
outpatient unit at our institute due to persistent bilious
Insulin I [8, 16] emesis, abdominal pain, weight loss, muscular wasting, and
Neutral Protamine Hagedorn (NPH) insulin daily sprouts of wheals in arms, legs, and torso, usually 30
s s minutes after the injection of insulin. The following findings
G I V E Q C C T S I C S L Y Q L E N Y C N were described after written consent was obtained from his
s s mother—his current legal guardian.
s s This child was the result of an uneventful pregnancy.
F V N Q H L C G S H L V E A L Y L V C G E R G F F Y T P K T
At birth, imperforate anus was diagnosed and corrected
I [8, 10, 11, 17] before 3 months of life. During his infancy, he achieved
Insulin all stages of neurological development satisfactorily. His
IV [18]
height—1.83 m—is a noteworthy trait since parents do not
Protamine I [8, 10, 19] exceed 1.70 m in this regard. Earliest manifestations of vitiligo
Lispro insulin (Humalog) were observed at 12 years of age, with symmetrical patches of
s s hypopigmented skin in ankles, knees, and hands (Figure 2).
G I V E Q C C T S I C S L Y Q L E N Y C N
s s
His family history includes a younger brother who was
s s
born with transient hypoglycemia, low birth weight, and
F V N Q H L C G S H L V E A L Y L V C G E R G F F Y T K P T multiform erythema and uncle from his mother side with
vitiligo.
I [8, 12, 15] His diabetic debut was further investigated and the
Insulin
III [15] mother was reinterrogated. During his first hyperglycemic
Aspart insulin (NovoLog) crisis—October 2012—he was brought to the ER with intense
s s tiredness, weight loss, polyuria, polydipsia, abdominal pain,
G I V E Q C C T S I C S L Y Q L E N Y C N emesis, and glucose levels >400 mg/mL. He was treated with
s s
s s
fluids and one Crystalline insulin 10 U IV bolus per hour until
F V N Q H L C G S H L V E A L Y L V C G E R G F F Y T K P T
normalization of glucose levels; afterwards, he was switched
to a bimodal schedule of SC insulin therapy: 5 U of Crystalline
Insulin I [8, 16, 20] preprandially and 14 U of NPH at bedtime. The first dose
4 Case Reports in Immunology

Table 2: Classification of autoimmune polyglandular syndromes (APS).

Category Subtypes Criteria

Two or more from the following
(i) Addison’s disease
(ii) Chronic candidiasis
(iii) Hypoparathyroidism
Associated conditions
APS-1 (i) Alopecia
—
(ii) Autoimmune gastritis/pernicious anemia
(iii) Type 1 diabetes
(iv) Vitiligo
(v) Autoimmune thyroid disease
(vi) Chronic hepatitis
(vii) Autoimmune-related gonadal failure
Addison’s disease plus any of the following
APS-2 — (i) Type 1 diabetes
(ii) Autoimmune thyroid disease
Autoimmune thyroid disease plus: type 1 diabetes with/without any other endocrine
organ involvement
Autoimmune thyroid disease plus: autoimmune gastrohepatic disease
(inflammatory bowel syndrome, pernicious anemia, autoimmune gastritis, and
APS-3A
primary biliary cirrhosis)
APS-3 APS-3B
Autoimmune thyroid disease plus: skin autoimmune disease (vitiligo with/without
APS-3C
alopecia areata) with/without nervous system autoimmune disease (miastenia
APS-3D
gravis, multiple sclerosis)
Autoimmune thyroid disease plus: rheumatological autoimmune disease (systemic
and discoid lupus, rheumatoid arthritis, Sjögren syndrome, systemic sclerosis,
vasculitis, and antiphospholipid syndrome) with/without hematological disease
APS-4 Any other combination of specific organ and nonorgan specific autoimmune
—
diseases

of NPH caused immediate hypersensitivity, with urticaria
lesions, pruritus, and low fever. Thus, this presentation was
omitted, and IV chlorpheniramine was used twice per day for
treatment of the allergic reaction; he was discharged 3 days
later with SC Crystalline as sole treatment, at a dosage of 15 U
30 minutes prior to each meal.
Two weeks later, in November 2012, the patient returns
to the local ER with moderate dehydration, multiple emesis,
abdominal pain, and polyuria. He was started on fluids,
empirical antibiotic therapy, and IV Crystalline boluses, and
after normalization of glucose levels, he was administered
32 U of Glargine SC which induced an immediate anaphy-
lactoid reaction with angioedema, wheezing, shortness of
breath, and pruritic rash. He was treated with IV hydrocor-
tisone (1 g) and chlorpheniramine (10 mg), and the allergic
symptoms remitted after 36 hours. He was discharged again
1 week later with SC Lispro (Humalog, 18 U 15 minutes
prior to every meal) insulin as treatment. During the first
weeks of December 2012, the mother started to notice small
urticaria lesions on her son’s legs and torso 2 hours after
insulin injection, which disappeared with the use of common
oral antihistamines such as Loratadine. However, she became
aware that the dosage for insulin appeared insufficient and
had to be increased progressively in order to try and achieve
glycemic control, but skin lesions were spreading further
around his body.
During the final week of December 2012, the patient was
referred to the University Hospital in the city of Maracaibo
due to hyperglycemia, ketoacidosis, profound weight loss (20
kilograms since October 2012), muscular wasting, and gen-
eral malaise. During physical examination the following was
observed: profuse diaphoresis, pale skin, abdominal disten-
tion and flatulence, no signs of neurological focalization, or
disorientation; respiratory rate: 22 bpm, heart rate: 121 bpm,
blood pressure: 100/60 mmHg, and temperature: 36.8∘ C;
regarding anthropometric measurements, height: 183 cm,
weight: 47 kg, arm span: 185 cm, and BMI: 14.07 kg/m2 .
He was admitted with a diagnosis of diabetic ketoacidosis
and treated with both 100 U of Crystalline insulin diluted
in 500 cc of 0.9% saline solution at a rate of 5 UI/kg/h
and chlorpheniramine (10 mg) STAT intravenously. After 4
hours, glucose levels normalized and no signs of allergy
were observed. However, the following day the patient
develops symptomatic hypoglycemia and insulin treatment
is modified. A bimodal scheme is installed with 5 U SC of
Crystalline insulin preprandially, maintaining the dose of IV
chlorpheniramine every 12 hours. Forty-eight hours later, no
skin lesions resembling hypersensitivity were observed, but
glycemic control was suboptimal, with reports of preprandial
glycemia between 250–480 mg/dL at noon. Insulin therapy
was then further modified to include a 15 U prebreakfast
bolus of Crystalline insulin, 5 U before lunch and before
Case Reports in Immunology
Figure 2: Hypochromic skin lesions associated with vitiligo.
dinner, and a final 10 U bedtime bolus of NPH insulin, both
SC. However, this schedule was omitted immediately because
the patient developed angioedema with the first dose of NPH.
It is after this last hypersensitivity episode that our
Endocrinology and Immunology Departments were asked
to evaluate the case. A Prick Test with different types
of insulin was performed in order to determine which
preparation would be most appropriate for the patient. All
commercially available presentations were used with the
exception of Aspart (NovoRapid) insulin (which was not
available in the city at the time). The test was positive
for NPH and Lispro, while it was negative for Glargine,
Detemir (Levemir), and glulisine (Apidra). Insulin therapy
was then started with a basal-bolus scheme: glulisine 10 U SC
preprandially and Detemir 20 U SC at bedtime, accompanied
with 10 mg of Ebastine p.o. every 8 hours, and 10 mg of
Prednisone p.o. once per day. Normalization of glycemic
values was obtained with this scheme with no allergic skin
lesions, so the patient was discharged. During hospitaliza-
tion, several laboratory panels were undertaken to further
investigate insulin allergy and to exclude involvement of
autoimmunity in other glands, which would suggest diag-
nosis of APS (Table 3); these explorations returned positive
5
for autoimmune gastritis/pernicious anemia. Additionally, he
was evaluated for Marfan’s syndrome due to his height and
arm span measurements; however ophthalmologic, radio-
logic, and cardiologic testing ruled out this diagnosis. One
week after discharge, the patient attends emergency services
again due to pruriginous papules in the neck, thorax, and
limbs that appeared approximately 45 minutes after the
Detemir injections (Figure 3), and one event during dinner-
time injection associated with intense pruritus with glulisine
dosage. In light of these findings, a desensitization protocol
was conceived and applied.
The desensitization protocol is described in Table 4. The
purpose of this therapy is to induce skin anergy by multiple
and increasing dosages of insulin until a given dosage of
the medication is tolerated by cutaneous immunocytes. Since
the patient tolerated Crystalline via SC, we decided to use
Glargine insulin because of local availability and economic
factors. The protocol included premedication with 10 mg of
Ebastine and 60 mg of Prednisone 30 minutes before the
first dose. Glargine was administered intradermally in the
abdominal region every 20 minutes for 5 days; see Table 3 for
dosages. The goal of the procedure was to induce tolerance to
dosages of 12 U Glargine, given twice almost simultaneously
6 Case Reports in Immunology

Table 3: Complementary laboratory workup.

Results Reference values

Immunoglobulin E (IgE) 140.60 IU/mL 0–150 IU/mL
Immunoglobulin A (IgA) 1 g/L 0.60–3.09 g/liter
Immunoglobulin M (IgM) 245 mg/dL 40–250 mg/dL
Immunoglobulin G (IgG) 1529 mg/dL 710–1520 mg/dL
Fasting C peptide 0.14 ng/mL 0.9–7.1 ng/mL
Cortisol (AM) 42.5 30–150 ng/mL
Free triiodothyronine (FT3) 1.9 pg/mL 1.4–4.2 pg/mL
Free thyroxine (FT4) 1.1 0.89–1.76 ng/mL
Thyroid stimulating hormone (TSH) 0.945 𝜇IU/mL 0.3–4.00 mUI/mL
Anti-thyroglobulin antibody 7.0 IU/mL <10 IU/mL
Anti-thyroperoxidase antibody 10.1 IU/mL <30 IU/mL
Parietal cell autoantibody Positive
Intrinsic factor autoantibody Positive
Anti-gliadin antibodies Negative
Anti-transglutaminase antibodies Negative
Anti-Saccharomyces antibodies Negative

to achieve a total of 24 U of this insulin per day in two Table 4: Desensitization protocol using Glargine insulin.
different body regions. The dose of Prednisone was then
lowered to 30 mg during days 2 and 3 and suspended on day Day Number ∗of Accumulated Total dosage Local reaction
dosages dose (IU) per day (IU) (cm) ¶
4; glucocorticoid therapy lasted a total of 4 days. The patient
was discharged seven days after admission. One year later, 1 1 0,001 0,001 1
he is stable and without any flaring event, studying second 1 2 0,01 0,011 0
semester at community college. Currently assisting to the 1 3 0,1 0,111 1,5
outpatient consults every 4 months. 1 4 1 1,111 0
1 5 2 3,111 0
2 6 0,1 0,1 1
3. Discussion 2 7 1 1,1 0
Insulin allergy is a rare and complex complication of insulin 2 8 2 3,1 0
therapy in diabetic patients, with a current estimated preva- 2 9 3 6,1 0
lence of approximately 2.4% [8], depending on case reports in 3 10 2 2 0
type 1 and type 2 diabetes mellitus patients. The importance 3 11 3 5 0
of insulin allergy relies on its fundamental role as a lifelong
3 12 4 9 0
treatment. Several cases have been documented on diabetic
patients, allergic to Glargine [32, 33], Detemir [34, 35], 4 13 12 12 0
Crystalline [14, 36], NPH [14, 37], Aspart [14], Lispro [33], all 5 14 12 12 0
available insulins [8, 12, 15, 38], and even components of such 5 15∘ 12 24 0
medications such as metacresol [24] and protamine [10, 19, ∗
Time between injections: 20 minutes.
33], with or without presence of beta-lactam antibiotic allergy ∘
Administrated almost simultaneously with dosage number 14, in a different
[12]. Clinical presentation varies, from local cutaneous lesions corporal region.
¶
to anaphylactic shock, either IgE- or IgG-mediated [39]; see Diameter of the flare.
Figure 1. Type I allergy reactions are IgE-dependent, induced
by the insulin molecule or other components, activating the
allergy-related pathway. Nevertheless, IgG-mediated insulin and anticomponent IgG titers. In the present case, we assessed
allergy has also been reported [15, 40]. a young man who had acute presentation symptoms when
Heinzerling et al. [39] proposed a diagnostic flowchart, treated with Glargine, NPH, Lispro, Detemir, and Glulisine,
suggesting manifestations related to the acute presentation which evolved over a period of approximately 3 months.
(urticaria, rash, angioedema, dyspnea, nausea, diarrhea, and When insulin allergy is diagnosed, the general recommen-
cardiovascular manifestations) are likely to be IgE-mediated dation is to change to another insulin preparation and
and suggest the need for skin prick testing and assessment observe tolerance, which in this case failed in each attempt,
of IgE-insulin-specific titers. On the other hand, type IV demonstrated by cutaneous manifestations and severe inade-
late signs such as induration and erythema at injection site quate glycemic control. An important limitation in this case,
suggest IgG-mediated allergy, relating to specific antiinsulin was the lack of quantification of insulin-specific IgE/IgG
Case Reports in Immunology
Figure 3: Allergic reaction to Detemir. Note distribution of wheals and flares, as well as angioedema of lips and eyelids.
antibodies, as these assay kits are not available in our country.
It is noteworthy to comment about the results of the prick
test. Glargine was negative in this test, even though he had
experienced hypersensitivity to this type of insulin when
injected with 32 U. We propose that negativity for this insulin
might be due to (a) very high dosage used in this primary
treatment which might have caused an adverse drug reaction,
or (b) Glargine allergy-induction needs higher doses than
the one used in the prick test. Previous case reports have
suggested that insulin-related allergy depends on dosage,
route of administration, and type of insulin and these account
for discrepancies observed between allergenic crisis and skin
testing [14, 39, 41].
Given the escalating insulin allergy events observed, a
desensitization protocol was planned with Glargine, a long-
lasting insulin formulation that is easily available in the
country. The purpose of this protocol is to control local forms
of insulin allergy, inducing anergy in skin immunocytes [26].
Other protocols have used Glargine [33, 39, 41] and other
7
insulin analogs, such as Aspart [8, 24] for their desensitization
therapy, either using continuous infusion [24, 40, 41] or
intradermal injections, all of them achieving immunological
control and metabolic improvement.
To our knowledge, this is the first documented case of
insulin allergy in type 4 APS. Both clinical entities share sim-
ilar immunogenetics: insulin immunogenicity is intimately
related to T1DM pathogenesis [42] and might share HLA hap-
lotypes with APS. Although HLA-B15-DR4 boasts an impor-
tant association with hyperimmune manifestations [43],
insulin-allergic subjects exhibit a greater prevalence of HLA-
Bw44, HLA-DR7, and HLA-A2 and their combinations, with
a RR of 20.6 for developing an allergy/immune reaction to
insulin [44] and the presence of a specific immune response
gene for insulin [43]. On the other hand, APS encompasses
a constellation of immunogenic diseases (Table 2) whose
presentation and severity rely on the convergence of pre-
disposing and protective HLA haplotypes. In regards to
the present case (APS-4: vitiligo + T1DM + autoimmune
8 Case Reports in Immunology
gastritis/pernicious anemia), vitiligo has been associated with
cytotoxic T lymphocyte-mediated melanocyte destruction in
patients positive for HLA-A2 [45], HLA-DRB1∗07-DQB1∗02
[46], and HLA-B∗44:03/DRB1∗07:01 [47]. As for T1DM,
several alleles have been proposed, and although they appear
to be highly ethnicity-specific, HLA-A2 [48], HLA-DR4-
DQ8, and DR3-DQ2 [49] are the most prevalent world-
wide. Lastly, autoimmune gastritis has been described to
be mainly associated with DRB1∗1101/DQA1∗0505 [50] and
HLA-DRB1∗04/DQB1∗03 [51], whereas pernicious anemia is
associated with higher prevalence of HLA-D/DR3 and HLA-
DR5 [52].
Cases of APS type 4 have been published previously,
although with different combinations when compared to
ours. Krysiak et al. [53] published a case concerning primary
hypoparathyroidism and T1DM, associated with positive
anti-transglutaminase and anti-parietal cell antibodies, while
Hsu et al. [54] reported a peculiar case of T1DM, anti-GAD-
related dystonia, vitiligo, alopecia areata, and myasthenia
gravis. The present case is characterized by the primary devel-
opment of vitiligo, followed by T1DM, and the detection of
autoimmune gastritis/pernicious anemia while investigating
insulin allergy, making this case one of a kind.
4. Conclusions
Insulin allergy is considered a rare complication during
insulin therapy, yet it should always be suspected in patients
with nonspecific cutaneous and systemic symptoms after
insulin injections, where appropriate insulin-specific IgE
assays should be carried out. The presence of two or more
autoimmune-related diseases must prompt further evalua-
tion for other affected organs and classification of the patient.
Ultimately, this scenario begs the question: is insulin allergy
a sign of an underlying major autoimmune disease, such
as APS and nonconventional organ-specific autoimmunity?
Further immunogenetic and pathophysiologic studies may
help clarify this enigma, especially in the case of this pair
of disorders, which seem to be more prevalent in current
medical practice.
Conflict of Interests
The authors declare that there is no conflict of interests
regarding the publication of this paper.
References
[1] American Diabetes Association, “Executive summary: stan-
dards of medical care in diabetes—2014,” Diabetes Care, vol. 37,
supplement 1, pp. S5–S13, 2014.
[2] J.-W. Yoon and H.-S. Jun, “Autoimmune destruction of pancre-
atic 𝛽 cells,” American Journal of Therapeutics, vol. 12, no. 6, pp.
580–591, 2005.
[3] M. Aguirre, J. Rojas, R. Cano, M. Villalobos, and L.
Berrueta, “Diabetes mellitus tipo 1 y factores ambientales:
la gran emboscada,” Revista Venezolana de Endocrinologı́a y
Metabolismo, vol. 10, pp. 122–134, 2012.
[4] T. L. van Belle, K. T. Coppieters, and M. G. von Herrath, “Type
1 diabetes: etiology, immunology, and therapeutic strategies,”
Physiological Reviews, vol. 91, no. 1, pp. 79–118, 2011.
[5] G. Schernthaner, “Immunogenicity and allergenic potential of
animal and human insulins,” Diabetes Care, vol. 16, no. 3, pp.
155–165, 1993.
[6] R. Patterson, M. RobertsI, and L. C. Grammer, “Insulin allergy:
re-evaluation after two decades,” Annals of Allergy, vol. 64, no.
5, pp. 459–462, 1990.
[7] M. K. Ghazavi and G. A. Johnston, “Insulin allergy,” Clinics in
Dermatology, vol. 29, no. 3, pp. 300–305, 2011.
[8] V. Matheu, E. Perez, M. Hernández et al., “Insulin allergy and
resistance successfully treated by desensitisation with Aspart
insulin,” Clinical and Molecular Allergy, vol. 3, article 16, 2005.
[9] A.-Y. Lee, W.-Y. Chey, J. Choi, and J.-S. Jeon, “Insulin-induced
drug eruptions and reliability of skin tests,” Acta Dermato-
Venereologica, vol. 82, no. 2, pp. 114–117, 2002.
[10] M. E. Bollinger, R. G. Hamilton, and R. A. Wood, “Protamine
allergy as a complication of insulin hypersensitivity: a case
report,” Journal of Allergy and Clinical Immunology, vol. 104, no.
2, pp. 462–465, 1999.
[11] A. Teixeira Rodrigues, L. F. Chiaverini Ensina, L. Sabino
Garro, L. Kase Tanno, P. Giavina-Bianchi, and A. Abilio Motta,
“Human insulin allergy: four case reports,” European Annals of
Allergy and Clinical Immunology, vol. 42, no. 6, pp. 221–223,
2010.
[12] P. Andrade, L. Barros, and M. Gonçalo, “Type 1 Ig-E mediated
allergy to human insulin, insulin analogues and beta-lactam
antibiotics,” Anais Brasileiros de Dermatologia, vol. 87, no. 6, pp.
917–919, 2012.
[13] J. H. Hong, J. H. Lee, J. H. Shin et al., “Maintenance of insulin
therapy by desensitization in insulin allergy patient,” Korean
Diabetes Journal, vol. 32, pp. 529–531, 2008.
[14] H. Yokoyama, S. Fukumoto, H. Koyama, M. Emoto, Y. Kita-
gawa, and Y. Nishizawa, “Insulin allergy; desensitization with
crystalline zinc-insulin and steroid tapering,” Diabetes Research
and Clinical Practice, vol. 61, no. 3, pp. 161–166, 2003.
[15] C. Pföhler, C. S. L. Müller, D. O. Hasselmann, and W. Tilgen,
“Successful desensitization with human insulin in a patient with
an insulin allergy and hypersensitivity to protamine: a case
report,” Journal of Medical Case Reports, vol. 2, article 283, 2008.
[16] P. J. Raubenheimer and N. S. Levitt, “Insulin allergy,” South
African Medical Journal, vol. 94, no. 6, pp. 428–429, 2004.
[17] K.-N. Durand-Gonzalez, N. Guillausseau, C. Pecquet, and J.-P.
Gayno, “Glargine insulin is not an alternative in insulin allergy,”
Diabetes Care, vol. 26, no. 7, article 2216, 2003.
[18] M. Maheshwari, D. Goyal, P. Desouza, and R. K. Goyal, “Spotted
dermopathy in a diabetic patient due to insulin allergy,” Journal
of Association of Physicians of India, vol. 52, pp. 926–927, 2004.
[19] Y. Q. Chu, L. J. Cai, D. C. Jiang, D. Jia, S. Y. Yan, and Y. Q.
Wang, “Allergic shock and death associated with protamine
administration in a diabetic patient,” Clinical Therapeutics, vol.
32, no. 10, pp. 1729–1732, 2010.
[20] “Insulin detemir/insulin glargine/insulin protamine aspart,”
Reactions Weekly, no. 1412, p. 26, 2012.
[21] E. Alfadhli, “Allergy to insulin glargine: a case report,” Journal
of Medical Cases, vol. 2, pp. 4–6, 2011.
[22] A. Sola-Gazagnes, C. Pecquet, J. M’Bemba, E. Larger, and G.
Slama, “Type I and type IV allergy to the insulin analogue
detemir,” The Lancet, vol. 369, no. 9562, pp. 637–638, 2007.
Case Reports in Immunology
[23] P. Darmon, V. Castera, M.-C. Koeppel, C. Petitjean, and A.
Dutour, “Type III allergy to insulin detemir,” Diabetes Care, vol.
28, no. 12, article 2980, 2005.
[24] B. J. Wheeler and B. J. Taylor, “Successful management of
allergy to the insulin excipient metacresol in a child with type 1
diabetes: a case report,” Journal of Medical Case Reports, vol. 6,
article 263, 2012.
[25] M. E. R. Silva, M. J. M. Mendes, M. J. M. Ursich et al.,
“Human insulin allergy-immediate and late type III reactions in
a long-standing IDDM patient,” Diabetes Research and Clinical
Practice, vol. 36, no. 2, pp. 67–70, 1997.
[26] I. Eguı́luz-Gracia, M. Rodrı́guez-Álvarez, M. Cimarra-Álvarez,
M. C. Sanabria-Pérez, and C. Martı́nez-Cócera, “Desensitiza-
tion for Insulin allergy: a useful treatment also for local forms,”
Journal of Investigational Allergology and Clinical Immunology,
vol. 22, no. 3, pp. 215–235, 2012.
[27] R. Begum, Y. S. Marfatia, N. C. Laddha, M. Dwivedi, M. S.
Mansuri, and M. Singh, “Vitiligo: a complex disease and a
complex approach,” Molecular Cytogenetics, vol. 7, article I57,
2014.
[28] N. Karsli, C. Akcali, O. Ozgoztasi, N. Kirtak, and S. Inaloz, “Role
of oxidative stress in the pathogenesis of vitiligo with special
emphasis on the antioxidant action of narrowband ultraviolet
B phototherapy,” Journal of International Medical Research, vol.
42, pp. 799–805, 2014.
[29] B. X. Zhang, M. Lin, X. Y. Qi et al., “Characterization of
circulating CD8+T cells expressing skin homing and cytotoxic
molecules in active non-segmental vitiligo,” European Journal of
Dermatology, vol. 23, no. 3, pp. 331–338, 2013.
[30] A. van den Driessche, V. Eenkhoorn, L. van Gaal, and C.
de Block, “Type 1 diabetes and autoimmune polyglandular
syndrome: a clinical review,” Netherlands Journal of Medicine,
vol. 67, no. 11, pp. 376–387, 2009.
[31] G. J. Kahaly, “Polyendocrine autoimmune syndromes,” Euro-
pean Journal of Endocrinology, vol. 61, pp. 11–20, 2009.
[32] G. Petrovski, M. Zivkovic, T. Milenkovic, I. Ahmeti, and
I. Bitovska, “Successful desensitization in patient with type
2 diabetes with an insulin allergy using insulin pump and
glargine,” Acta Diabetologica, 2014.
[33] C. Hasselmann, C. Pecquet, E. Bismuth et al., “Continuous
subcutaneous insulin infusion allows tolerance induction and
diabetes treatment in a type 1 diabetic child with insulin allergy,”
Diabetes & Metabolism, vol. 39, no. 2, pp. 174–177, 2013.
[34] M. P. Aujero, S. Brooks, N. Li, and S. Venna, “Severe serum
sickness-like type III reaction to insulin detemir,” Journal of the
American Academy of Dermatology, vol. 64, no. 6, pp. e127–e128,
2011.
[35] S. Ghosh, V. McCann, L. Bartle, A. Collier, and I. Malik, “Allergy
to insulin detemir,” Diabetic Medicine, vol. 24, no. 11, p. 1307,
2007.
[36] H. Takatsuki, H. Ishii, T. Yamauchi et al., “A case of insulin
allergy: the crystalline human insulin may mask its antigenic-
ity,” Diabetes Research and Clinical Practice, vol. 12, no. 2, pp.
137–139, 1991.
[37] C. Blanco, R. Castillo, J. Quiralte et al., “Anaphylaxis to subcuta-
neous neutral protamine Hagedorn insulin with simultaneous
sensitization to protamine and insulin,” Allergy: European
Journal of Allergy and Clinical Immunology, vol. 51, no. 6, pp.
421–424, 1996.
[38] M. A. Mollar-Puchades and I. L. Villanueva, “Insulin glulisine
in the treatment of allergy to rapid acting insulin and its rapid
9
acting analogs,” Diabetes Research and Clinical Practice, vol. 83,
no. 1, pp. e21–e22, 2009.
[39] L. Heinzerling, K. Raile, H. Rochlitz, T. Zuberbier, and M.
Worm, “Insulin allergy: clinical manifestations and manage-
ment strategies,” Allergy, vol. 63, no. 2, pp. 148–155, 2008.
[40] M. F. Madero, J. Sastre, J. Carnés, S. Quirce, and J. L. Herrera-
Pombo, “IgG4-mediated allergic reaction to glargine insulin,”
Allergy, vol. 61, no. 8, pp. 1022–1023, 2006.
[41] M. Asai, M. Yoshida, and Y. Miura, “Immunologic tolerance
to intravenously injected insulin,” The New England Journal of
Medicine, vol. 354, no. 3, pp. 307–309, 2006.
[42] V. M. Cambuli, M. Incani, E. Cossu et al., “Prevalence of type 1
diabetes autoantibodies (GADA, IA2, and IAA) in overweight
and obese children,” Diabetes Care, vol. 33, no. 4, pp. 820–822,
2010.
[43] B. Bruni, P. Barolo, G. Gadaleta et al., “HLA typing and insulin
antibody production in insulin-dependent diabetics,” Annali
dell’Ospedale Maria Vittoria di Torino, vol. 27, no. 7–12, pp. 185–
213, 1984.
[44] C. R. Kahn, D. Mann, A. S. Rosenthal, J. A. Galloway, A. H.
Johnson, and N. Mendell, “The immune response to insulin in
man. Interaction of HLA alloantigens and the development of
the immune response,” Diabetes, vol. 31, no. 8, pp. 716–723, 1982.
[45] R. L. Mandelcorn-Monson, N. H. Shear, E. Yau et al., “Cyto-
toxic T lymphocyte reactivity to gp100, MelanA/MART-1, and
tyrosinase, in HLA-A2-positive vitiligo patients,” Journal of
Investigative Dermatology, vol. 121, no. 3, pp. 550–556, 2003.
[46] A. Bouayad, L. Benzekri, S. Hamada, C. Brick, B. Hassam, and
M. Essakalli, “Association of HLA alleles and haplotypes with
vitiligo in Moroccan patients: a case-control study,” Archives of
Dermatological Research, vol. 305, no. 10, pp. 925–932, 2013.
[47] A. Singh, P. Sharma, H. K. Kar et al., “HLA alleles and
amino-acid signatures of the peptide-binding pockets of HLA
molecules in vitiligo,” The Journal of Investigative Dermatology,
vol. 132, no. 1, pp. 124–134, 2012.
[48] P. van Endert, Y. Hassainya, V. Lindo et al., “HLA class I epitope
discovery in type 1 diabetes,” Annals of the New York Academy
of Sciences, vol. 1079, pp. 190–197, 2006.
[49] A. Huber, F. Menconi, S. Corathers, E. M. Jacobson, and Y.
Tomer, “Joint genetic susceptibility to type 1 diabetes and
autoimmune thyroiditis: from epidemiology to mechanisms,”
Endocrine Reviews, vol. 29, no. 6, pp. 697–725, 2008.
[50] H.-W. Lee, K.-B. Hahm, J. S. Lee, Y.-S. Ju, K. M. Lee, and K.
W. Lee, “Association of the human leukocyte antigen class II
alleles with chronic atrophic gastritis and gastric carcinoma in
Koreans,” Journal of Digestive Diseases, vol. 10, no. 4, pp. 265–
271, 2009.
[51] A. M. Oksanen, K. E. Haimila, H. I. K. Rautelin, and J.
A. Partanen, “Immunogenetic characteristics of patients with
autoimmune gastritis,” World Journal of Gastroenterology, vol.
16, no. 3, pp. 354–358, 2010.
[52] M. Thomsen, F. Jørgensen, M. Brandsborg et al., “Association of
pernicious anemia and intrinsic factor antibody with HLA-D,”
Tissue Antigens, vol. 17, no. 1, pp. 97–103, 1981.
[53] R. Krysiak, I. Kobielusz-Gembala, and B. Okopień, “Atypical
clinical presentation of autoimmune polyglandular syndrome
type 4,” Przegla¸d Lekarski, vol. 68, no. 6, pp. 339–341, 2011.
[54] Y.-T. Hsu, J.-R. Duann, M.-K. Lu, M.-C. Sun, and C.-H.
Tsai, “Polyglandular autoimmune syndrome type 4 with GAD
antibody and dystonia,” Clinical Neurology and Neurosurgery,
vol. 114, no. 7, pp. 1024–1026, 2012.
Copyright of Case Reports in Immunology is the property of Hindawi Publishing Corporation
and its content may not be copied or emailed to multiple sites or posted to a listserv without
the copyright holder's express written permission. However, users may print, download, or
email articles for individual use.